PMID- 30258047 OWN - NLM STAT- MEDLINE DCOM- 20191113 LR - 20240213 IS - 2041-4889 (Electronic) VI - 9 IP - 10 DP - 2018 Sep 26 TI - Neuroprotection of retinal ganglion cells by a novel gene therapy construct that achieves sustained enhancement of brain-derived neurotrophic factor/tropomyosin-related kinase receptor-B signaling. PG - 1007 LID - 10.1038/s41419-018-1041-8 [doi] LID - 1007 AB - Previous studies have demonstrated that intravitreal delivery of brain-derived neurotrophic factor (BDNF) by injection of recombinant protein or by gene therapy can alleviate retinal ganglion cell (RGC) loss after optic nerve injury. BDNF gene therapy can improve RGC survival in experimental models of glaucoma, the leading cause of irreversible blindness worldwide. However, the therapeutic efficacy of BDNF supplementation alone is time limited at least in part due to BDNF receptor downregulation. Tropomyosin-related receptor kinase-B (TrkB) downregulation has been reported in many neurological diseases including glaucoma, potentially limiting the effect of sustained or repeated BDNF delivery.Here, we characterize a novel adeno-associated virus (AAV) gene therapy (AAV2 TrkB-2A-mBDNF) that not only increases BDNF production but also improves long-term neuroprotective signaling by increasing expression of the BDNF receptor (TrkB) within the inner retina. This approach leads to significant and sustained elevation of survival signaling pathways ERK and AKT within RGCs over 6 months and avoids the receptor downregulation which we observe with treatment with AAV2 BDNF alone. We validate the neuroprotective efficacy of AAV2 TrkB-2A-mBDNF in a mouse model of optic nerve injury, where it outperforms conventional AAV2 BDNF or AAV2 TrkB therapy, before showing powerful proof of concept neuroprotection of RGCs and axons in a rat model of chronic intraocular pressure (IOP) elevation. We also show that there are no adverse effects of the vector on retinal structure or function as assessed by histology and electroretinography in young or aged animals. Further studies are underway to explore the potential of this vector as a candidate for progression into clinical studies to protect RGCs in patients with glaucoma and progressive visual loss despite conventional IOP-lowering treatment. FAU - Osborne, Andrew AU - Osborne A AD - John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. AD - Quethera Ltd, Babraham Research Campus, Cambridge, UK. FAU - Khatib, Tasneem Z AU - Khatib TZ AD - John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. AD - Eye Department, Addenbrooke's Hospital, Cambridge, UK. FAU - Songra, Lalana AU - Songra L AD - John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. FAU - Barber, Amanda C AU - Barber AC AD - John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. FAU - Hall, Katie AU - Hall K AD - John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. FAU - Kong, George Y X AU - Kong GYX AD - Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia. AD - University of Melbourne, Melbourne, Australia. FAU - Widdowson, Peter S AU - Widdowson PS AD - Quethera Ltd, Babraham Research Campus, Cambridge, UK. FAU - Martin, Keith R AU - Martin KR AD - John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. krgm2@cam.ac.uk. AD - Quethera Ltd, Babraham Research Campus, Cambridge, UK. krgm2@cam.ac.uk. AD - Eye Department, Addenbrooke's Hospital, Cambridge, UK. krgm2@cam.ac.uk. AD - Cambridge NIHR Biomedical Research Centre, Cambridge, UK. krgm2@cam.ac.uk. AD - Wellcome Trust-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. krgm2@cam.ac.uk. LA - eng GR - WT_/Wellcome Trust/United Kingdom GR - MC_PC_12009/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180926 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Membrane Glycoproteins) RN - 7171WSG8A2 (BDNF protein, human) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 2.7.10.1 (tropomyosin-related kinase-B, human) SB - IM MH - Animals MH - Axons/pathology MH - Brain-Derived Neurotrophic Factor/*genetics MH - Dependovirus/genetics MH - Disease Models, Animal MH - Down-Regulation/genetics MH - Genetic Therapy/methods MH - Glaucoma/genetics/pathology MH - HEK293 Cells MH - Humans MH - Intraocular Pressure/genetics MH - Male MH - Membrane Glycoproteins/*genetics MH - Mice MH - Mice, Inbred C57BL MH - Neuroprotection/*genetics MH - Optic Nerve Injuries/genetics/pathology MH - Rats MH - Rats, Sprague-Dawley MH - Receptor, trkB/*genetics MH - Retina/pathology MH - Retinal Ganglion Cells/*pathology MH - Signal Transduction/*genetics PMC - PMC6158290 COIS- P.S.W. and K.R.M. have a financial interest in Quethera Ltd, a company working to develop gene therapy approaches to neurodegenerative diseases. A.O., K.H., and K.R.M. have received grant support from Quethera Ltd. T.Z.K., L.S., A.C.B., and G.Y.X.K. have no disclosures. EDAT- 2018/09/28 06:00 MHDA- 2019/11/14 06:00 PMCR- 2018/09/26 CRDT- 2018/09/28 06:00 PHST- 2018/04/06 00:00 [received] PHST- 2018/09/07 00:00 [accepted] PHST- 2018/09/04 00:00 [revised] PHST- 2018/09/28 06:00 [entrez] PHST- 2018/09/28 06:00 [pubmed] PHST- 2019/11/14 06:00 [medline] PHST- 2018/09/26 00:00 [pmc-release] AID - 10.1038/s41419-018-1041-8 [pii] AID - 1041 [pii] AID - 10.1038/s41419-018-1041-8 [doi] PST - epublish SO - Cell Death Dis. 2018 Sep 26;9(10):1007. doi: 10.1038/s41419-018-1041-8.